Targeting G protein‐coupled receptors for heart failure treatment

Heart failure remains a leading cause of morbidity and mortality worldwide. Current treatment for patients with heart failure include drugs targeting G protein‐coupled receptors such as β‐adrenoceptor antagonists (β‐blockers) and angiotensin II type 1 receptor antagonists (or angiotensin II receptor blockers). However, many patients progress to advanced heart failure with persistent symptoms, despite treatment with available therapeutics that have been shown to reduce mortality and mortality. GPCR targets currently being explored for the development of novel heart failure therapeutics include adenosine receptor, formyl peptide receptor, relaxin/insulin‐like family peptide receptor, vasopressin receptor, endothelin receptor and the glucagon‐like peptide 1 receptor. Many GPCR drug candidates are limited by insufficient efficacy and/or dose‐limiting unwanted effects. Understanding the current challenges hindering successful clinical translation and the potential to overcome existing limitations will facilitate the future development of novel heart failure therapeutics.

Patients are diagnosed with heart failure based on risk factors, symptoms and abnormal electrocardiogram readings followed by high Btype natriuretic peptide levels (Heidenreich et al., 2022).Irregular echocardiography outcomes define heart failure phenotypes based on left ventricular ejection fraction (LVEF).Patients can be clinically diagnosed with (i) heart failure with reduced ejection fraction with LVEF ≤40%, (ii) mid-range ejection fraction or mildly reduced ejection fraction with LVEF between 41% and 49%, (iii) heart failure with improved ejection fraction, patients in whom heart failure with reduced ejection fraction was previously manifested but where LVEF is now >40%) and/or (iv) heart failure with preserved ejection fraction with LVEF ≥50% (McDonagh et al., 2021;Yancy et al., 2013).The diagnosis of failure with preserved ejection fraction remains challenging, consisting of varied criteria such as objective evidence of abnormal cardiac structure and function in the presence of left ventricular diastolic dysfunction (Heidenreich et al., 2022;McDonagh et al., 2021).
Standard treatment for heart failure includes small-molecule drugs targeting G protein-coupled receptors (GPCRs), particularly β-adrenoceptor and angiotensin II type 1 (AT 1 ) receptor antagonists (McDonagh et al., 2021).Despite maximal therapy and improvement in survival rate, heart failure remains a leading cause of morbidity and mortality worldwide, with many heart failure patients progressing to advanced heart failure with persistent symptoms (Truby & Rogers, 2020).The mortality rate of heart failure patients remains at 40% within 5 years of diagnosis (Jones et al., 2019).As such, there remains an unmet clinical need to develop novel therapeutics to prevent or treat heart failure.Here we review current GPCR targets and more recent therapeutic avenues for heart failure treatment.

| G PROTEIN-COUPLED RECEPTOR INVOLVEMENT IN CURRENT HEART FAILURE TREATMENTS
Current GPCR therapeutics include β-antagonists, which target β-adrenoceptors, angiotensin II receptor antagonists which target angiotensin II receptors and an angiotensin receptor-neprilysin (neutral endopeptidase) inhibitor, a dual target medication (Figure 1).These GPCR pharmacotherapies reduce the risk of heart failure hospitalisations and improve clinical outcomes and survival rate (McDonagh et al., 2021).
β-adrenoceptor antagonists, clinically referred to as β-blockers, are commonly prescribed therapy for heart failure with reduced ejection fraction patients (Bangalore et al., 2014).The β-antagonists bisoprolol, carvedilol, metoprolol and nebivolol have been shown to improve clinical outcomes and reduce mortality (McDonagh et al., 2021).The European Society of Cardiology guidelines suggest that β-antagonists may also be considered for mid-range ejection fraction or mildly reduced ejection fraction patients, based on an individual participant data meta-analysis of landmark β-antagonist trials (McDonagh et al., 2021;van Veldhuisen et al., 2009).Clinically used β-adrenoceptor antagonists are considered to exert most of their effects through the β 1 -adrenoceptor, with two of the three Food and Drug Administration (FDA)-approved β-antagonists for the treatment of heart failure, metoprolol and bisoprolol, displaying approximately 100-fold β 1 :β 2 selectivity (Yoshikawa et al., 1996).Of note, the non-selective FDA-approved adrenoceptor antagonist carvedilol was shown to confer greater benefit on survival in chronic heart failure patients compared to metoprolol (Poole-Wilson et al., 2003), perhaps attributable to the down-regulation of myocardial β 1 -adrenoceptors in heart failure (Yoshikawa et al., 1996) and/or its unique suppression of reactive oxygen species (Dandona et al., 2000).As such, subsequent generations of β-antagonists that further fine-tune subtype selectivity and receptor pharmacology may provide an opportunity to develop adrenoceptor ligands with greater therapeutic efficacy.Regardless, β-antagonists remain standard therapy that confers clear benefits to heart failure patients.
Metoprolol has also been shown to promote β 1 -adrenoceptor biased signalling, inducing fibrotic gene expression in cardiomyocytes and subsequent cardiac dysfunction through G protein-independent signalling, namely G protein-coupled receptor kinase 5 and β-arrestin 2-dependent pathways (Nakaya et al., 2012).These findings highlight the range of mechanisms that can influence β-antagonist-mediated cardioprotection.
β-antagonists can mediate additional cardioprotective benefits to heart failure patients.Neurohormonal mechanisms inhibit noradrenaline and renin release from sympathetic neurons and juxtaglomerular apparatus, respectively (Kim et al., 2012;Rosen et al., 1990).
AT antagonists, commonly known as angiotensin II receptor blockers, improve clinical outcomes in heart failure patients.AT antagonists used therapeutically include candesartan, valsartan and losartan (McDonagh et al., 2021).In dog and rat models of MI, valsartan T A B L E 1 An overview of GPCR targets for the treatment of heart failure, including G protein coupling, signalling pathways and drugs targeting certain diseases/conditions with the highest status.Phase I-III (Balling et al., 2018;Gheorghiade et al., 2004;Goldsmith et al., 2021;Konstam et al., 2007;O'Connor et al., 2010); Chronic heart failure, HFpEF Phase I-III (Coletta et al., 2002;Kiowski et al., 1995;Kohan et al., 2012;Sütsch et al., 1998) significantly improved cardiac function and reduced infarct size and infarct expansion and thinning (Jugdutt & Menon, 2004).A systematic review of clinical studies showed that AT antagonists did not reduce morbidity and mortality in patients with heart failure.Compared with angiotensin-converting enzyme inhibitors, treatment with AT antagonists exhibited lower withdrawal due to adverse effects in patients with LVEF ≤40%.However, in patients with LVEF >40%, withdrawal due to adverse effects of AT antagonists were higher compared to placebo (Heran et al., 2012).Given the clinical outcomes and withdrawal rates due to adverse effects, AT antagonists are typically prescribed as a combination therapy (McDonagh et al., 2021).

| Combination therapy
Combination therapy is commonly recommended in patients with heart failure to substantially and sustainably reduce symptoms, mortality and heart failure hospitalisations (Bauersachs, 2021;McDonagh et al., 2021).β-antagonists can be used as first-line therapy, yet they may be more effective in reducing cardiovascular events and subsequent risk of death (Vögele et al., 2017).In routine clinical practice, a combined treatment of a β-antagonist with an ACE inhibitor or AT antagonist provides the lowest incidence of major adverse cardiovascular events, all-cause mortality and heart failure hospitalisation (McDonagh et al., 2021;Sim et al., 2020).
Recently, a combination therapy consisting of an angiotensin

| Adenosine receptors
Adenosine receptors have many important roles in physiology, including the regulation of heart rate, blood pressure, neuronal function and kidney diuresis.Adenosine receptors consist of four subtypes: A 1 receptor, A 2A receptor, A 2B receptor and A 3 receptor (Fredholm et al., 2011;Vecchio et al., 2018).Of particular interest as cardiovascular targets are the A 1 and A 2B receptors.A 1 receptors, expressed predominantly in cardiomyocytes, preferentially couples to G i/o proteins, whereas A 2B receptors, expressed predominantly in cardiac fibroblasts, preferentially couple to G s proteins, but can also couple to G q/11 or G i/o proteins (Fredholm et al., 2000;Fredholm et al., 2001;Gao et al., 1999;Gao et al., 2018).

| Adenosine A 2B receptor
The A 2B receptor can modulate cardiac fibrosis (Vecchio et al., 2019), a condition whereby fibroblast to myofibroblast transformation leads to excessive production, deposition and contraction of extracellular matrix proteins, leading to maladaptive fibrosis (Travers et al., 2016;Weber et al., 2012).Myofibroblasts produce less cAMP, an antifibrotic signalling molecule, due to decreased adenylate cyclase expression alongside increased cyclic nucleotide phosphodiesterase expression (Lu et al., 2013;Swaney et al., 2005).A 2B receptor activation stimulates G s protein coupling, enhancing cAMP accumulation to decrease pro-fibrotic signalling (Epperson et al., 2009;Feoktistov & Biaggioni, 1997;Vecchio et al., 2017).PKA and exchange protein activated by cAMP (Epac) are downstream effectors of adenylate cyclase-dependent cAMP accumulation (Cheng et al., 2008).The activation of these proteins inhibits cardiac fibrosis (Yokoyama et al., 2008).In particular, Epac can stimulate the activation of PI3K-Akt (Villarreal et al., 2009), leading to a decrease in collagen deposition, inhibition of collagen synthesis as well as differentiation of myofibroblasts (Phosri et al., 2017;Phosri et al., 2018).In isolated neonatal rat cardiac fibroblasts, A 2B receptor stimulation with the agonist VCP746 inhibited the collagen deposition caused by ang-II and transforming growth factor-β1 (Valant et al., 2014;Vecchio et al., 2016).Post-myocardial infarction, rats chronically treated with dipyridamole, an adenosine uptake inhibitor, and 2-chloroadenosine, a non-selective adenosine receptor agonist, showed improvements in haemodynamic and echocardiographic parameters with a reduction of collagen synthesis; effects that were diminished in the presence of an A 2B receptor selective antagonist MRS1754 (Wakeno et al., 2006).Activation of A 2B receptors can inhibit cardiac fibroblast proliferation and the synthesis of protein and collagen (Figure 1b) (Chen et al., 2004).Although A 2B receptor stimulation promotes cardioprotection, these effects may be reduced over time due to A 2B receptor downregulation (Asakura et al., 2007) and alterations in the expression of downstream signalling molecules (Liu et al., 2013;Swaney et al., 2005).A 2B receptors have also been associated with maladaptive fibrosis.In rodents, A 2B receptor inhibition post-MI prevented myocardial apoptosis, infiltration of leukocytes, expression of adhesion molecules, cardiac injury and fibrosis (Toldo et al., 2012;Zhang et al., 2014).Similarly, diastolic function was preserved in A 2B receptor knock-out mice subjected to permanent ligation of the left anterior descending coronary artery (Maas et al., 2008).
Highly expressed on the surface of endothelial cells (Hassanian et al., 2014), A 2B receptors also regulate endothelial inflammatory responses by suppressing the expression of adhesion molecules, such as intercellular adhesion molecule-1 and E-selectin, on endothelial cells resulting in prevention of rolling, adhesion and transmigration of leukocytes during acute inflammation (Hassanian et al., 2014;Yang et al., 2006).Given the diverse A 2B receptor signalling, a greater understanding of the molecular mechanisms underpinning A 2B receptor modulation of cardiac fibrosis and cardiac function post-MI is required prior to developing A 2B receptor therapeutics.

| Adenosine receptor ligands in clinical studies
Adenosine receptor agonists have entered clinical trials for cardiovascular conditions (Jacobson et al., 2019).A randomised, doubleblind, multicentre, placebo-controlled trial called AMP579 Delivery for Myocardial Infarction REduction study (ADMIRE) reported that AMP579, an A 1 receptor/A 2A receptor agonist, did not reduce the final infarct size in MI patients with an age range of 31-85, where 16% were diabetic (Kopecky et al., 2003).In contrast, adenosine infusion at 70 μgÁkg À1 Ámin À1 reduced infarct size in patients (median   et al., 1999).The AMISTAD-II with a larger sample size of 2118 MI patients (median age of 60 years, 15-17% diabetic) showed that infusion of adenosine at 70 μgÁkg À1 Ámin À1 , but not at 50 μgÁkg À1 Ámin À1 , significantly reduced infarct size.Moreover, a strong relationship was found between infarct size and the primary clinical endpoint (death or heart failure).However, the study was underpowered to demonstrate a clinical benefit for the higher dose (70 μgÁkg À1 Ámin À1 ) alone (Ross et al., 2005).As such, higher dose adenosine (70 μgÁkg À1 Ámin À1 ) appears to confer adenosine receptormediated cardioprotection in humans.However, alternative approaches such as biased agonism, that can selectively stimulate A 1 receptor cardioprotective signalling with minimal activation of unwanted on-target effects, may be better suited for effective translation through clinical trials (Baltos et al., 2016;Valant et al., 2014;Vecchio et al., 2018).
Recently an A 1 receptor partial agonist neladenoson (Rueda et al., 2020) was trialled in patients with chronic heart failure with reduced ejection fraction (67.2 of age, 39.3% were diabetic).Outcomes from the PANTHEON trial showed A 1 receptor partial agonism could not significantly improve cardiac function or clinical outcomes in an advanced heart failure cohort (Voors et al., 2019).In addition, a higher proportion of patients experienced adverse events, such as hypotension and atrioventricular block (Voors et al., 2019).These trials demonstrate that A 1 receptor partial agonists, which by definition have limited receptor efficacy, cannot reverse late-stage heart failure.Higher efficacy adenosine receptor agonists, particularly biased agonists, administered at an earlier phase of heart failure development would likely be better placed to significantly improve clinical outcomes.
An FPR1/FPR2 dual agonist compound 17b demonstrated significant cardioprotection, reducing the release of cardiac troponin I and expression of TGFβ-induced pro-fibrotic connective tissue growth factor and pro-inflammatory interleukin-1β (IL-1β) in isolated primary cardiomyocytes and cardiac fibroblasts (Figure 1) (Qin et al., 2017).In a left anterior descending coronary artery permanent occlusion mouse model, compound 17b significantly decreased infarct size and cardiac remodelling (Qin et al., 2017).Further, another FPR1/FPR2 dual agonist, compound 43, also prevented cardiac remodelling and improved cardiac function in a mouse MI model (García et al., 2019).Recently, an FPR2 selective agonist, BMS-986235 (also known as LAR-1219), was shown to inhibit in vitro neutrophil chemotaxis and induce macrophage phagocytosis, reduce infarct size and improve cardiac function in a mouse heart failure model (Asahina et al., 2020;García et al., 2021).The cardioprotective effects of FPR2 agonism were attenuated in the presence of an FPR2 antagonist, WRW4 (Kain et al., 2019).WRW4 administration reduced FRP2 expression and dysregulated cytokine-chemokine kinetics, promoting the infiltration of immature and inactive neutrophils.WRW4 administration inhibited the resolution of inflammation, with mice developing acute heart failure post-MI in a model of permanent left anterior descending coronary artery ligation (Kain et al., 2019).Collectively studies suggest activation of FPR1 and/or FPR2 can promote cardioprotective effects.
Compounds targeting FPR have also been evaluated in early clinical trials.The FPR2 selective agonists ACT-389949 and BMS-986235 have progressed to Phase I trials.ACT-389949 was shown to be safe and well-tolerated in healthy individuals but caused a dose-dependent and long-lasting internalisation of cell surface FPR2 (Stalder et al., 2017).BMS-986235 trial results have not been released (ClinicalTrials.govIdentifier NCT03335553).Given the cardioprotective effects observed in vitro and in vivo, pharmacological targeting of FPRs may be a novel therapeutical approach for heart failure treatment, particularly when inflammation contributes to the disease pathology.
The antifibrotic effects of relaxin-2 have been studied in the context of cardiovascular disease.In rat cardiac fibroblasts, relaxin inhibited angiotensin II-and insulin-like growth factor 1-induced fibroblast proliferation, suppressed the differentiation of fibroblasts into myofibroblasts and increased matrix metalloproteinase 2 expression in response to angiotensin II and TGF-β (Samuel et al., 2004).Relaxin was shown to activate the nitric oxide/cGMP pathway in rat hearts (Bani et al., 1998) and rat cardiac fibroblasts (Samuel et al., 2004).
Given the beneficial effects of relaxin, a recombinant form of human relaxin-2, serelaxin, which primarily binds to RXFP1 (Díez & Ruilope, 2016), was developed as a potential therapeutic agent.In the Relaxin in Acute Heart Failure (RELAX-AHF) double-blind placebocontrolled trial, 48 h serelaxin infusion (30 μgÁkg À1 per day) demonstrated a lower incidence of worsening heart failure and a survival benefit at 180 days in acute heart failure patients (Teerlink et al., 2013).However, in a larger RELAX-AHF2 trial, the same serelaxin dose and infusion rate did not confer significant protection (Metra et al., 2019).Therefore, despite initial promising results as a new heart failure treatment, the future progression of RXFP therapeutics remains uncertain.
The small molecule RXFP1 agonist, ML290, can stimulate similar responses to relaxin (Martin et al., 2019;Xiao et al., 2010).Despite having a biased profile relative to relaxin in cell based assays, ML290 stimulates anti-fibrotic signalling, inhibiting TGF-β1-stimulated Smad2 and Smad3 phosphorylation in human cardiac fibroblasts (Kocan et al., 2017).ML290 may be a potential RXFP1 drug candidate for the treatment of heart failure.

| Vasopressin receptors
Heart failure is associated with elevated plasma levels of vasopressin (Goldsmith et al., 1983;Iovino et al., 2018).Vasopressin is synthesised and secreted from the hypothalamus, acting through the vasopressin receptor family of GPCRs.Vasopressin receptors ) are primarily expressed in the heart, kidney, bladder, spleen and vascular smooth muscle cells.Upon activation, vasopressin receptors mediate vasoconstriction, water reabsorption, cardiovascular control and homeostasis (Holmes et al., 2003).Therefore, elevated vasopressin levels in heart failure cause vasoconstriction and antidiuresis, leading to peripheral oedema, a syndrome of salt and water retention.
Highly expressed in vascular smooth muscle cells and the heart, V 1 receptor preferentially couples to G q/11 proteins (Table 1), which regulate phospholipase C activity (Barberis et al., 1998).Studies have shown that activation of V 1 receptor can promote several detrimental effects in vivo.Cardiac hypertrophy, as well as left ventricular dilation and dysfunction, were observed in mice with myocardial overexpression of V 1 receptor (Li et al., 2011), indicating a role of V 1 receptor in heart failure development (Figure 1A).The effects were diminished by transgenic inhibition of G q protein signalling (Li et al., 2011).Cardiac hypertrophy was significantly attenuated in V 1 receptor-knockout mice subjected to transverse aortic constriction compared to wildtype mice (Hiroyama et al., 2007).Treatment with V 1 receptor selective antagonists, such as OPC-21268 and relcovaptan (SR490590), attenuated vasopressin-mediated detrimental effects and preserved cardiac function in transverse aortic constriction-mice (Hiroyama et al., 2007;Tilley et al., 2014).Moreover, deletion or acute inhibition of V 1 receptor was shown to improve β-adrenoceptor activity and sensitivity (Tilley et al., 2014;Wasilewski et al., 2016).These studies indicate that V 1 receptor activation can mediate detrimental cardiac effects, with V 1 antagonism preventing cardiac remodelling and heart failure progression.
The V 2 receptor is highly expressed in renal endothelial cells and is pleiotropically coupled to different G proteins, including G s , G i/o , G q/11 and G 12/13 (Table 1) (Heydenreich et al., 2021).Through G sprotein coupling, V 2 receptor activation stimulates cAMP production, which promotes water reabsorption (Harris et al., 1994).V 2 receptor activation causes in vivo cardiac remodelling and cardiac dysfunction, with effects abrogated by a V 2 receptor antagonist.In a rat MI model, the selective V 2 antagonist tolvaptan significantly improved ejection fraction and attenuated MI-induced inflammation and interstitial fibrosis (Yamazaki et al., 2012).Moreover, in a rat hypertensive heart failure model, chronic treatment with a higher dose of tolvaptan improved survival rate and renal function without affecting blood pressure, compared to the lower tolvaptan dose (Morooka et al., 2012).These studies suggest V 2 antagonists should confer cardiac and renal protective effects.
Clinical trials of dual vasopressin receptor antagonists and V 2 selective antagonists have been conducted to treat heart failure.The ACTIV in chronic heart failure trial demonstrated that the selective V 2 antagonist tolvaptan reduced mortality in heart failure patients with renal dysfunction and severe systemic congestion (Gheorghiade et al., 2004).However, in the larger EVEREST trial, tolvaptan did not affect long-term mortality or morbidity related to heart failure (Konstam et al., 2007;O'Connor et al., 2010).Tolvaptan is currently being evaluated as early add-on therapy for overcoming loop diuretic resistance in acute heart failure patients with renal dysfunction (ClinicalTrials.govIdentifier NCT04331132).A randomised, doubleblind single-centre study of a dual V 1 /V 2 -receptor antagonist conivaptan infusion (20 mgÁml À1 ) in heart failure patients with LVEF <45% found no significant improvement in exercise cardiac output, compared to placebo-treated patients (Balling et al., 2018).More recently, the dual V 1 /V 2 -receptor antagonist pecavaptan (also known as BAY1753011), investigated in the AVANTI trial, enhanced decongestion in patients with acute heart failure (Goldsmith et al., 2021).To date, vasopressin receptor antagonists have not transitioned into the clinic as a heart failure treatment, likely due to mixed outcomes from clinical trials.

| Endothelin receptors
In heart failure, many different neuro-hormonal systems, such as the renin-angiotensin system and endothelin (ET) system, are progressively activated to maintain initial circulatory homeostasis.Similar to the renin-angiotensin system, the ET system also has vasoconstrictive, anti-natriuretic and mitogenic properties (Giannitsis & Katus, 2013).
ET is a strong independent predictor of death post-MI and in congestive heart failure where patients with congestive heart failure significantly have high plasma levels of ET (McMurray et al., 1992;Rodeheffer et al., 1992).
ET is a potent vasoconstrictive peptide of 21 amino acids, which has three isoforms, named ET-1, ET-2 and ET-3 (Davenport et al., 2016).The ET isoforms can activate two types of ET receptors expressed on vascular smooth muscle cells, including ET type A receptor and ET type B receptor, which pleiotropically couple to G s , G i/o , G q/11/13 proteins (Table 1) (Liu & Wu, 2003;Shraga-Levine & Sokolovsky, 2000;Takigawa et al., 1995).ET A receptor is preferentially activated by ET-1 with the rank order of potency being ET-1 > ET-2 ) ET-3, whereas the ET isoforms elicit similar binding affinity at ET B receptor (Davenport, 2002;Masaki, 1998).Activation of ET A receptor mediates vasoconstriction, cell proliferation and myocardial effects (Kohan et al., 2012).Whereas activation of ET B receptor can promote nitric oxide-and prostacyclin (PGI 2 )-mediated vasodilation and clearance of plasma ET in the lung (Kohan et al., 2012;Spieker et al., 2001).Locally generated in the heart by cardiomyocytes, stimulated by ang-II, ET-1 acts as an autocrine/paracrine factor in cardiomyocyte hypertrophy via activation of ET A receptor.The underlying mechanism of this pathophysiological condition has been proposed to be via ERK1/2 phosphorylation and the stress-activated protein kinase (SAPK; JNK2) family (belonged to MAP kinases) pathway (Figure 1a) (Archer et al., 2017;Choukroun et al., 1998).In cardiac fibroblasts, ET-1 elicits PKC-dependent fibrotic signalling and gene expression (Figure 1b) (Piacentini et al., 2000).Therefore, ET A and ET B antagonism has been explored to treat heart failure.
Endothelin receptor antagonists (ERAs) have been studied in vivo and in clinical trials, including selective ET A or ET B antagonists or nonselective ET antagonists (Spieker et al., 2001).One of the earliest orally active ET A/B antagonist, bosentan, also known as RO 47-0203, significantly increased survival through a long-term treatment in a rat model of chronic heart failure by improving cardiac function and reducing cardiac remodelling (Mulder et al., 1997).Given the in vivo cardioprotective properties, bosentan has undergone several clinical trials where it showed haemodynamic benefits, reductions in both systemic and pulmonary vascular resistances and arterial pressures, and improvement in cardiac output (Kiowski et al., 1995;Sütsch et al., 1998).However, short-term bosentan treatment significantly increased plasma ET-1 levels in patients (Kiowski et al., 1995;Sütsch et al., 1998).Lower dose bosentan was used in the ENABLE (1&2) trial in a larger patient cohort.However, treatment groups showed no difference in death, heart failure hospitalisation and all-cause mortality.
Moreover, adverse effects, including fluid-retention-induced weight gain and peripheral oedema were reported (Coletta et al., 2002;Kohan et al., 2012)  3.6 | Glucagon-like peptide-1 (GLP-1) receptor Heart failure is a secondary complication of many metabolic diseases, particularly diabetes and obesity.FDA-approved antidiabetic therapeutics have been shown to be cardioprotective where they significantly reduce cardiovascular risks and outcomes (Cosentino et al., 2020).The class B GPCR, GLP-1 receptor preferentially couples to G s proteins, with additional coupling to G i and G q proteins (Wootten et al., 2017).GLP-1 receptor activation results in insulin priming and insulin granule exocytosis in pancreatic β cells (Wootten et al., 2017).
GLP-1 agonists, including exenatide, liraglutide, semaglutide and dulaglutide, have been assessed for decreasing cardiovascular events in diabetic patients (Cosentino et al., 2020;Kreiner et al., 2022).In the LEADER trial, liraglutide significantly reduced cardiovascular and allcause deaths at 3.1 years in patients with type 2 diabetes and high cardiovascular risk (Marso et al., 2016).Similarly, the Peptide Innovation for Early Diabetes Treatment (PIONEER)-6 trial demonstrated a significant reduction relative to placebo in cardiovascular and all-cause death in semaglutide-treated diabetic patients with high cardiovascular risk (Husain et al., 2019).The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) study in diabetic patients found exenatide a relative risk reduction for MACE in the exenatide-treated subgroup with known cardiovascular disease (Cosentino et al., 2020).
However, the LIVE study on chronic heart failure patients with and without diabetes found that liraglutide did not improve left ventricular ejection fraction compared to placebo (Jorsal et al., 2017).
Similarly, no significant effect of liraglutide on post-hospitalization clinical stability was reported in a study assessing the functional impact of GLP-1 agonists for heart failure treatment (FIGHT study) in 300 patients with established heart failure with reduced ejection fraction (Margulies et al., 2016).As such, whilst GLP-1 agonists appear to reduce cardiovascular and all-cause deaths in diabetic patients, current evidence does not show an effect on incident heart failure.Cardioprotective actions of GLP-1 agonists, at least on the context of diabetes, are thought to be evident at the level of atherothrombotic events rather than heart failure events (Marx et al., 2022).Therefore, GLP-1 agonists are not currently recommended as a treatment to prevent heart failure events (McDonagh et al., 2021).
Additional studies are required to better understand the cardiovascular effects of GLP-1 agonists, including both direct and indirect effects.
The extended half-lives of GLP-1 agonists may contribute to their beneficial cardiovascular effects (McDonagh et al., 2021).Current studies suggest GLP-1 agonists predominantly confer cardiovascular benefit by decreasing atherosclerosis-related events (Kreiner et al., 2022).However, different GLP-1 agonists can have distinct activation profiles (Zhang et al., 2020) and as such, the influence of different GLP-1 agonists in the treatment of heart failure deserves further exploration.

| Conclusion
There remains an unmet clinical need for more effective heart failure treatments, as heart failure remains a leading cause of morbidity and mortality worldwide (Taylor et al., 2017).New therapeutic targets to prevent progressive heart failure are being continually explored.Therapeutic candidates targeting various GPCRs, such as adenosine receptors, formyl peptide receptors, relaxin receptors, vasopressin receptors, endothelin receptors and the glucagon-like peptide-1 receptor have undergone clinical trials.None of these candidates has progressed to the clinic, predominantly due to the lack of efficacy and/or adverse effects.The challenge in transitioning heart failure pharmacotherapies from the bench to bedside may be facilitated through a greater understanding of disease mechanisms, harnessing new approaches to fine-tune GPCR activity and optimising the translational pathway from preclinical studies to clinical trials (Figtree et al., 2021;Lane et al., 2017).

| Nomenclature of targets and ligands
Key protein targets and ligands in this article are hyperlinked to corresponding entries in the IUPHAR/BPS Guide to PHARMACOLOGY http://www.guidetopharmacology.org and are permanently archived in the Concise Guide to PHARMACOLOGY 2021/22 (Alexander, Christopoulos, et al., 2021;Alexander, Fabbro, et al., 2021).
receptor and a neprilysin inhibitor (ARNI) was approved for use in heart failure patients.Heart failure activates the natriuretic peptide system, increasing brain natriuretic peptide expression.Brain natriuretic peptides negatively regulate the detrimental effects of the renin-angiotensin system(Baba et al., 2019); however, they are broken down by neprilysin [neutral endopeptidase](Jhund & McMurray, 2016).To counteract the negative effects of neprilysin, the angiotensin receptor-neprilysin (neutral endopeptidase) inhibitor combination medicine was recently FDA-approved for patients with heart failure with reduced ejection fraction(Sauer et al., 2018).The dual treatment angiotensin receptor-neprilysin inhibitor consists of a neprilysin inhibitor, sacubitril, and an AT antagonist, valsartan.Clinical trials have demonstrated the combination treatment was superior to enalapril in reducing the risk of death and heart failure hospitalisation in patients with heart failure with reduced ejection fraction (LVEF ≤ 40%)(McMurray et al., 2014;Nielsen et al., 2020).However, compared to enalapril-treated patients, sacubitril/ valsartan treatment was associated with a higher proportion of adverse effects, including hypotension and nonserious angioedema(McMurray et al., 2014).Sacubitril/valsartan was recommended to supersede adrenoceptor antagonist and ACE inhibitors for patients with heart failure with reduced ejection fraction(Nielsen et al., 2020).Due to their dual complementary actions, combination therapy is routinely used in clinical practice(McDonagh et al., 2021).However, even patients on combination therapy have a low survival rate of approximately 52% 5 years after diagnosis(Taylor et al., 2017).Hence, better treatments for heart failure are required.

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| NEW GPCR TARGETS IN THE DRUG DISCOVERY PIPELINE Novel therapeutic targets are being explored with the aim to provide additional effective treatment options for heart failure patients.GPCRs of particular interest include adenosine receptors, formyl peptide receptors, relaxin/insulin-like family peptide receptors, vasopressin (V) receptors, endothelin (ET) receptors and the glucagon-like peptide 1 (GLP-1) receptor (Figure2).
age of 57 years; 16%-21% diabetic) in the Acute Myocardial Infarction Study of Adenosine (AMISTAD) trial.The AMISTAD trial had a relatively small sample size (n = 236) that limited the assessment of adenosine on clinical outcomes and patients experienced more adverse events, such as hypotension and bradycardia (Mahaffey treatment, however, the study was prematurely terminated due to patient recruitment (ClinicalTrials.govIdentifier: NCT03153111).An open-label extension trial was also discontinued due to the primary efficacy outcome measure not being met (ClinicalTrials.govIdentifier: NCT03714815).Due to dose limiting adverse effects and currently unknown outcomes of clinical trials, ERAs have not yet successfully transitioned into the clinic as a heart failure treatment.
. Post the ENABLE trial, botensan has entered a (Kohan et al., 2012)tagonists, including enrasentan and darusentan have also entered clinical trials.However, these ET antagonists exhibited adverse effects and no cardiac remodelling benefit(Kohan et al., 2012).The ET antagonist macitentan, FDA-approved to treat pulmonary arterial hypertension, entered a Phase II trial to evaluate drug efficacy and safety for failure with preserved ejection fraction